Persistent Pulmonary Hypertension Among Infants Undergoing Therapeutic Hypothermia for Hypoxic Ischemic Encephalopathy: A Systematic Review and Meta-Analysis

Abstract

To perform a systematic review and meta-analysis to examine the association between persistent pulmonary hypertension (PPHN) and receipt of therapeutic hypothermia (TH), compared to those who did not receive TH, among infants with moderate or severe hypoxic-ischemic encephalopathy (HIE). Systematic review and meta-analysis based on Ovid, Medline, Embase and Cochrane central searches from 01/01/2000 to 31/03/2025. We included only randomized control trials for meta-analysis and followed international guidelines for conducting systematic reviews. The primary outcome of the study was PPHN in infants undergoing TH for moderate to severe HIE. Among 185 articles identified using search strategy, 19 articles were assessed for eligibility. Eight randomized control trials (RCTs) met the inclusion criteria, and seven were included in meta-analysis. A random effects model used for the outcome of PPHN, comparing TH with NT or usual care, involving a pooled population of 1006 infants across seven studies. The relative risk of PPHN for TH versus NT was 1.13 (95% confidence interval 0.81 to 1.57). We noted risk of bias in the blinding of participants across included RCTs. We assessed nine observational studies and performed a narrative review. We noted that a considerable number of infants developed PPHN across TH and NT groups. We did not find evidence of an association between TH and PPHN in infants with moderate to severe HIE, although a considerable number of infants developed PPHN across both groups. We suggest that clinicians should be aware of the risk of PPHN to allow prompt investigation and management.